Heart failure remains one of the leading causes of mortality in the developed world. Whereas the mammalian heart is endowed with certain regenerative potential, endogenous cardiomyocyte proliferation is insufficient for functional heart repair upon injury. Interestingly, non-mammalian vertebrates, such as the zebrafish, can regenerate the damaged heart by inducing cardiomyocyte dedifferentiation and proliferation. By screening regenerating zebrafish hearts Applicants identified miR-99/100 down-regulation as a key process driving cardiomyocyte dedifferentiation. Experimental down-regulation of miR-99/100 in primary adult murine and human cardiomyocytes led to an increase in the number of proliferating cardiomyocytes. AAV-mediated in vivo down-regulation of miR-99/100 after acute myocardial injury in mice induced mature cardiomyocyte proliferation, diminished infarct size and improved heart function. Applicants' study unveils conserved regenerative mechanisms between zebrafish and mammalian cardiomyocytes and represents a proof-of-concept on the suitability of activating pro-regenerative responses for healing the diseased mammalian heart.